21-43104346-G-T

Variant names:

• chr21-43104346-G-T
• rs371769427
• NM_006758.3:c.101C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_006758.3(U2AF1):​c.101C>A​(p.Ser34Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05
• Publications: 320 publications found

Genes affected

U2AF1 (HGNC:12453): (U2 small nuclear RNA auxiliary factor 1) This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.8478 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006758.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1	NM_006758.3	MANE Select	c.101C>A	p.Ser34Tyr	missense	Exon 2 of 8	NP_006749.1
	U2AF1	NM_001025203.1		c.101C>A	p.Ser34Tyr	missense	Exon 2 of 8	NP_001020374.1
	U2AF1	NM_001025204.2		c.-186C>A		5_prime_UTR	Exon 2 of 9	NP_001020375.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1	ENST00000291552.9	TSL:1 MANE Select	c.101C>A	p.Ser34Tyr	missense	Exon 2 of 8	ENSP00000291552.4
	U2AF1	ENST00000380276.6	TSL:1	c.101C>A	p.Ser34Tyr	missense	Exon 2 of 8	ENSP00000369629.2
	U2AF1	ENST00000464750.5	TSL:1	n.101C>A		non_coding_transcript_exon	Exon 2 of 9	ENSP00000420672.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249860 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.84		Loss of disorder (P = 0.0292)
MVP		0.75
MPC		3.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.99
Mutation Taster		=151/149	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371769427; hg19: chr21-44524456; COSMIC: COSV52341472; COSMIC: COSV52341472;